Van Leusen Imidazole Synthesis
Van Leusen Reaction
Synthesis of oxazoles
Van Leusen Oxazole Synthesis
The Van Leusen Oxazole Synthesis allows the preparation of oxazoles from aldehydes by reaction with tosylmethyl isocyanide (TosMIC).
Mechanism of the Van Leusen Oxazole Synthesis
The reaction is driven by the unique reactivity of TosMIC, which includes acidic protons, sulfinic acid as a leaving group and an isocyano group that contains an oxidizable carbon atom:
After adding the deprotonated TosMIC to the aldehyde and bond formation between the resulting hydroxy group and the isocyano group, an oxazoline results as an intermediate:
Within contrast to the Van-Leusen Reaction (synthesis of nitriles from ketones), the existence of a proton in the β-position to the sulfinyl group allows a base-promoted elimination:
A mechanism can be found in a publication by Van Leusen (Tetrahedron Lett., 1972, 13, 3114-3118. DOI).
The in situ formation of aldimines by reaction of aldehydes and an amine, and subsequent reaction with TosMIC, allows a synthesis of imidazoles (Van Leusen Three-Component Reaction).
Solution-phase parallel oxazole synthesis with TosMIC
B. A. Kulkarnia, A. Ganesan, Tetrahedron Lett., 1999, 40, 5637-5638.
One-Pot Van Leusen Synthesis of 4,5-Disubstituted Oxazoles in Ionic Liquids
B. Wu, J. Wen, J. Zhang, J. Li, Y.-Z. Xiang, X.-Q. Yu, Synlett, 2009, 500-504.
A One-Pot Tandem Approach for the Synthesis of 5-(Het)aryloxazoles from Substituted (Het)aryl Methyl Alcohols and Benzyl Bromides
K. S. V. Kumar, T. R. Swaroop, N. Rajeev, A. C. Vinayaka, G. S. Lingaraju, K. S. Rangappa, M. P. Sadashiva, Synlett, 2016, 27, 1363-1366.